Exploring Short-Acting Hormonal Contraceptives in Endometriosis Care-A Narrative Review and Evidence-Based Practical Considerations

Endometriosis is a chronic, estrogen-dependent inflammatory condition affecting around 10% of women of reproductive age worldwide. 1 It is characterized by the presence of endometrial-like tissue outside the uterine cavity—most commonly on the pelvic peritoneum and ovaries— although lesions can also occur in the bladder, bowel, and even extra-pelvic locations such as the diaphragm or lungs. 2 Clinically, endometriosis can manifest with dysmenorrhea, intermenstrual chronic pelvic pain, dyspareunia, fatigue, and infertility, placing a significant physical, emotional, and economic burden on affected individuals. 3 Despite being classified as a non-malignant condition, endometriosis is associated with a disproportionate impact on quality of life, social functioning, and work productivity and was ranked in 2021 as the second leading cause of gynecological disease-related morbidity globally. 4 , 5 The inherent heterogeneity of the disease is reflected in its diverse clinical presentations and complex physiopathology, characterized by reduced estrogen receptor alpha (ERα), mediating progesterone resistance and variable expression of estrogen receptor beta (ERβ) across lesion types. 3 This imbalance contributes to persistent inflammation, aberrant tissue remodeling, and lesion survival. 2 Other mechanisms, including estrogen-driven angiogenesis, immune dysfunction, and oxidative stress, further promote disease progression. 6 , 7 Elevated reactive oxygen species within the peritoneal cavity—derived from macrophages, eosinophils, and neutrophils—activate proliferative pathways and support ectopic cell survival. 7 – 9 Management of endometriosis is complex and individualized. As the condition has no definitive cure, current treatment goals focus on alleviating symptoms, controlling disease progression, improving fertility when desired, and enhancing quality of life. 10 Hormonal therapies and surgery constitute the main strategies for pain management, though both can interfere with fertility. Current guidelines, such as ESHRE 2022, NICE 2020 recommend hormonal treatments (combined oral contraceptives, progestogens) and/or NSAIDs as initial management options, though evidence quality is generally low to moderate. 10 – 17 The primary mechanism of action for the hormonal component involves the progestin, which mediates therapeutic effectiveness by inducing decidualization and atrophy in endometriotic lesions through progestogenic antimitotic activity. 18 They exert anti-inflammatory and anti-angiogenic effects: down-regulation of inflammatory mediators, inhibition of matrix metalloproteinases, reduction of oxidative stress, and promotion of apoptosis in endometriotic cells. 19 Hormonal treatments are effective in symptom relief, long-term disease control, and recurrence prevention after surgery, although with recurrences if discontinued. Evidence suggests that hormonal treatments help manage symptoms by lowering estrogen levels, reducing lesion growth, and suppressing the menstrual cycle. 20 , 21 Despite this, up to 30% of women under treatment continue to experience significant pain, potentially due to progesterone resistance, central sensitization, or coexisting conditions such as gastrointestinal symptoms, sexual dysfunction, mental health disorders, migraines, or fibromyalgia. These factors underscore the complexity of management and the need for personalized strategies. 22 Short-acting contraceptives (SACs)—which include the oral contraceptive pill, progestin-only pill (POP), vaginal ring, and patches 23 are among the most widely prescribed hormonal treatments for women of reproductive age. While their primary indication remains contraception, SACs have long been used off-label in the management of endometriosis-related symptoms due to their ability to regulate menstrual cycles, suppressing menses and ovulation, and reduce estrogen stimulation. 18 Indeed, SACs are effective first-line treatments for endometriosis-related pain, improving dysmenorrhea, pelvic pain, and dyspareunia. 24 , 25 Despite its widespread use and perceived benefit beyond contraception, evidence remains limited regarding the use of different formulations and dosing schedules ( e.g., progestin type, estrogen dose, continuous vs. cyclic regime), modes of administration, and dosing regimens. Moreover, few studies have explored whether tailoring SAC regimens can improve treatment adherence, symptom relief, and overall patient satisfaction in this population. In this context, there is a need to better understand and define the benefits of SACs beyond contraception in the treatment of endometriosis. This narrative review is part of the broader Agnodice project, 21 which compiled evidence on the benefits beyond contraception of different SAC formulations. The present review specifically focuses on SAC benefits on the management of endometriosis, aiming to support informed, women-centered counseling in clinical practice and to offer practical considerations to guide clinical decision-making.

In Agnodice Project, 21 a total of 86 systematic reviews/meta-analysis were reviewed and analyzed, giving 250 items, that is, data comparing two or more interventions for a particular clinical benefit in a specific population. However, only 138 items (from 70 articles) reported statistically significant differences between the compared interventions, and they were finally described in the Agnodice review. 21 Among the 70 articles, 10 articles reported information on the benefits of SAC on endometriosis symptoms and are included in the present review (see Fig. 1 ). All articles were systematic reviews and/or meta-analyses and can be found in Supplementary Table S2 . In the data extraction, the 10 articles included 21 significant items of information, i.e., data comparing two or more interventions for a particular endometriosis-related symptom. Among the 21 items extracted, 8 compared two or more SAC formulations, and 13 compared SAC vs placebo or no pharmacological treatment ( Fig. 1 ). The items that showed no significant differences are included in Supplementary Table S3 . Flow chart of included studies. **“Item’ refers to data comparing two or more interventions within a specific population, examining specific clinical benefits and outcomes. “Not significant” refers to those comparisons that did not find differences in the effects of the compared interventions ( p value <0.05). Data was presented as a narrative review due to the heterogeneity of available evidence (differences in study designs, outcome measures, and populations). From the 21 significant comparisons extracted, a total of 13 compared SAC vs placebo or no pharmacological treatment. The intervention with SAC demonstrated superiority for various formulations in 13 cases including ethinylestradiol (EE)/drospirenone (DRSP) (3 items), EE/norethisterone (NET) (2 items), EE/gestodene (GSD) (1 item), EE/desogestrel (DSG) (1 item), and oral contraceptives (OCs) in general (5 items), especially in continuous regime (1 item) ( Supplementary Table S4 ). Beyond the individual comparisons by specific formulations, these findings are consistent with a class effect of SACs, resulting in a clinically meaningful reduction observed across formulations in post-operative endometriosis recurrence (7 items) endometriosis-related pain (3 items), epithelial ovarian carcinomas (1 item) and various (gastrointestinal symptoms, reduction of ovarian endometrioma, migraine attacks, etc. ) (2 items) ( Supplementary Table S4 ). Nevertheless, some variability between regimens ( e.g., continuous vs. cyclic use) and progestin-related properties may modulate the magnitude of the effect. Among the 21 significant items extracted, 8 compared two or more SAC formulations, demonstrating significant superiority of one of the options. Most of the items reported information on endometriosis-related pain (dysmenorrhea), followed by various symptoms, including gastrointestinal symptoms, reduction of ovarian endometrioma, migraine attacks, etc. The results of reported SAC benefits on endometriosis-related symptoms by formulation are summarized in Table 2 . Summary of Preferred SAC Formulations for Endometriosis Similar pain relief in both groups. Higher frequency of breakthrough bleeding with DSG. Greater women satisfaction with DSG monotherapy (61.2% vs 37.8%). DSG associated with fewer contraindications than EE/DSG due to absence of thrombotic risk. Significantly higher rate of treatment satisfaction and satisfaction with changes in gastrointestinal symptoms with DSG compared with EE/ENG. Discontinuation was not significantly different for a continuous vs. cyclic treatment (RR 1.74; 95% CI 0.83 to 3.64; p = 0.14). Patient satisfaction rates were reported only in one study (12), with non significant differences between the two schedules. The column corresponding to the most effective SAC formulation is shown in bold to aid readability. For the purpose of this analysis, tolerability was operationally defined to include treatment continuation/discontinuation, adverse event (AE) profile and clinical safety, bleeding pattern alterations, and patient-reported experience and perception. DNG, dienogest; DSG, desogestrel; EE, ethinyl estradiol; ENG, etonogestrel; NA, not available; NET, norethisterone; NS, not specified; OCs, oral contraceptives; SAC, short-acting contraceptives. DSG alone was the formulation showing higher effectiveness in more outcomes and comparisons, and the 75 mg dose was the most commonly used in the studies. Firstly, when compared with EE/etonogestrel (ENG), DSG alone demonstrated significantly higher efficacy for endometriosis-related pain, 25 and it also showed superiority over EE/ENG for addressing gastrointestinal symptoms. 24 Secondly, when compared with EE/DSG, DSG alone was significantly more effective in various outcomes (rate of satisfaction, intensity of chronic pelvic pain, dyspareunia, and migraine attacks). 24 Notably, 61.2% of women in DSG group were satisfied with treatment compared with just 37.8% in the extended combined OC group. 24 Both groups showed significant reductions in chronic pelvic pain and dyspareunia at 24 weeks, with the DSG group also reporting fewer and less intense migraine attacks compared with baseline. 24 Lastly, when DSG was compared with EE/NET, DSG demonstrated superiority in improving non-menstrual pelvic pain, with a ranking p -score of 0.94 (DSG) versus 0.91 (EE/NET). 26 However, EE/NET was more effective than DSG and placebo for managing dysmenorrhea symptoms (dysmenorrhea score) in women with endometriosis, with a p -score of 0.97 (EE/NET) versus 0.53 (DSG). 26 EE/dienogest (DNG) on continuous regime was superior to cyclic EE/DNG for addressing endometriosis-related pain. The continuous use resulted in a significant reduction in pain from baseline, measured by the visual analog scale (VAS) at both 3 and 6 months, while significant improvement with cyclic use was seen only at 6 months. Between-group comparisons significantly favored the continuous versus the cyclic regime in quality-of-life results. 25 OCs on continuous regime were significantly more effective than cyclic OCs in reducing dysmenorrhea recurrence after surgery, with a relative risk of 0.24 (95% CI: 0.06 to 0.91; p = 0.04). 27 Current research does not indicate any significant differences in clinical outcomes related to the dose of SACs. Notably, all combined interventions included in the available studies used EE doses ranging from 15 to 35 µg per tablet.

All authors have made substantial contributions to the conception and design of the work, have drafted the initial version of the article, critically revised the article for its intellectual content, approved the final version of the article, and agreed to be accountable for all aspects of the work.

This review provides an updated synthesis of the available evidence regarding the non-contraceptive benefits of SACs in the management of endometriosis. Among 86 studies previously selected under the Agnodice Project for exploring SAC benefits beyond contraception, 10 systematic reviews and meta-analyses specifically addressed SAC use in endometriosis, leading to the identification of 21 relevant comparative items with significant differences. The findings suggest that SACs are effective first-line treatments for reducing symptoms associated with endometriosis, including dysmenorrhea, pelvic pain, dyspareunia, recurrence of endometriomas and endometriosis after surgery, and even potential risk reduction of epithelial ovarian carcinomas in women with endometriosis. In clinical practice, administration regimens—particularly the choice between continuous and cyclic use—play a key role in treatment outcomes. Importantly, continuous regimens of SACs demonstrated advantages compared with cyclic regimens, especially in terms of pain control, symptom recurrence, and health-related quality of life. These results align with prior research suggesting that eliminating or reducing withdrawal bleeding through continuous use can mitigate cyclical symptom flares and improve overall disease management. 27 – 31 Among SAC formulations, DSG alone showed superior outcomes in multiple comparisons. DSG was favored in most direct comparisons (5/8 items), including EE/DSG and EE/ENG, in managing chronic pelvic pain, dysmenorrhea, gastrointestinal symptoms, and migraine frequency, and it achieved higher patient satisfaction scores. This suggests that progestin-only options like DSG may represent a favorable therapeutic choice for patients who are either intolerant to estrogens or seeking alternatives with potentially fewer side effects. Nevertheless, combined formulations such as EE/DSG and EE/ENG also offer advantages in certain contexts, for example, in managing breakthrough bleeding or in patients with rectovaginal lesions, respectively. 24 DSG was found to be as effective as combined oral contraceptives in relieving pain symptoms after endometriosis surgery. 32 Molecular studies revealed that DSG treatment increased progesterone receptor and Bcl-2 expression while reducing Ki-67 expression in endometriotic tissue. 33 However, some studies suggest that DSG-containing pills may have a higher incidence of spotting and breakthrough bleeding compared with GSD-containing formulations, 34 although other research found similar rates. 35 Beyond clinical outcomes, it is important to recognize that different progestogens are characterized by distinct pharmacodynamic profiles, including antiandrogenic and antimineralocorticoid properties, as well as variable endometrial antiproliferative activity. For endometriosis, this last aspect—direct antiproliferative action on eutopic and ectopic endometrium—is particularly relevant. 19 Pharmacological heterogeneity may explain clinical differences. Oettel’s uterotropic index quantifies endometrial antiproliferative potency: DNG (16.7) > NETA (6.8) > DSG (3.0). 36 Although DSG shows clinical superiority in available systematic reviews and meta-analysis in the present review, higher-potency progestins warrant further study. Furthermore, in Schindler’s classification, DNG and NETA are among the progestins with the greatest potency for secretory transformation of the endometrium at contraceptive doses, whereas desogestrel is comparatively less potent in this regard. 37 Consistent with these pharmacological and clinical observations, in vitro studies have shown that DNG directly inhibits proliferation and promotes apoptosis in human endometrial stromal and epithelial cells through progesterone receptor-mediated mechanisms, including suppression of cyclin D1 expression. 38 , 39 Recent head-to-head evidence 40 complements these findings. In 714 patients across 8 RCTs, DNG 2 mg outperformed OCs for global VAS pain (SMD −1.46, p = 0.001) and quality of life (EHP-30, SF-12), though OCs were superior for dyspareunia (SMD 0.70) and pelvic pain. 40 Therefore, the dominant symptom profile should guide the initial choice between combined vs. progestin-only formulations. 40 Taken together, these pharmacological, clinical and molecular lines of evidence support the concept that DNG and NETA exert more pronounced direct tissue effects on endometrium and endometriotic foci than DSG, which may translate into stronger lesion atrophy and more sustained disease control in some patients. The findings of this review strongly align with major international guidelines. Both the European Society of Human Reproduction and Embryology (ESHRE) and the National Institute for Health and Care Excellence (NICE) guideline strongly recommend offering hormone treatment (such as combined hormonal contraceptives and progestogens) as a primary option to reduce endometriosis-associated pain in women with suspected or confirmed disease. 10 , 16 Specifically, the therapeutic superiority observed for continuous regimens of SACs in improving pain control and reducing symptom recurrence is supported by the ESHRE recommendation that women with dysmenorrhoea can be offered the continuous use of a combined hormonal contraceptive pill. 10 Both ESHRE and NICE mandate that clinicians adopt a shared decision-making approach, taking into account individual preferences, side effects, individual efficacy, costs, and availability when selecting hormonal treatments for pain. 10 , 16 Finally, the use of SACs postoperatively to prolong surgical benefits and manage symptoms 16 is consistent with guidelines recommending postoperative hormone treatment for the secondary prevention of recurrence. 10 Based on the evidence synthesized in this review, we present below 14 practical clinical considerations (see Supplementary Table S5 for further details) and an expert-opinion-based approach (see Fig. 2 ) for the use of SACs in endometriosis. Algorithm Endometriosis. Expert opinion-based practical medical approach to endometriosis management. CHC, combined hormonal contraceptives; CV, cardiovascular; POP, progestin-only pill. SACs as first-line hormonal therapy: SACs, including POP and CHCs, are recommended as initial hormonal treatment for endometriosis-related pain. 24 – 26 , 41 , 42 Class effect: Beyond the individual comparisons by specific formulations, all SACs included in this review result in a clinically meaningful reduction in post-operative endometriosis recurrence, endometriosis-related pain, epithelial ovarian carcinomas and various symptoms (gastrointestinal symptoms, reduction of ovarian endometrioma, migraine attacks, etc.). 24 , 41 – 46 Continuous vs cyclic regimen: Continuous combined regimens are preferred over cyclic schedules, as they eliminate menstrual bleeding and associated dysmenorrhea, and hence present superior pain control and reduced recurrence. 27 – 29 , 31 DSG 75 mg: Continuous desogestrel monotherapy is the preferred contraceptive option for endometriosis-related pain, pelvic pain, dyspareunia and other endometriosis-related symptoms (gastrointestinal symptoms, reduction of ovarian endometrioma, migraine attacks, etc.). 24 – 26 EE/NET: EE/NET is an alternative option, especially for endometriosis-related pain (dysmenorrhea), though less effective for broader pain symptoms (pelvic pain, dyspareunia…). 26 , 41 , 42 EE/DNG: Continuous EE/DNG is an effective combined option, improving endometriosis-related pain and quality of life. 25 EE/DRSP: Continuous EE/DRSP provides significant endometriosis-related pain reduction and decreases endometrioma recurrence compared with placebo/no treatment. 24 , 41 , 42 Formulation selection criteria: Choice of SAC should be individualized based on symptom profile, estrogen tolerance, cardiovascular risk, side-effect tolerance, patient preference, and reproductive plans. 16 , 24 , 25 , 47 Management of breakthrough bleeding/spotting in continuous SAC regimes: (1) Confirm adherence; (2) Provide counseling that improvement typically occurs by cycle 3–4; (3) For persistent breakthrough bleeding (≥5 consecutive days), consider: (a) short 3–4 day hormone-free interval, (b) tranexamic acid × 5 days, (c) formulation change to higher-dose estrogen or different progestin; (4) For spotting only, observe for 3–6 months before intervention. 27 , 34 , 35 Treatment duration: SACs should be continued after surgery. Long-term or indefinite use is recommended to prevent recurrence. 16 , 24 , 44 , 46 Therapeutic response and refractoriness: For refractory cases (about 30% may not respond), management includes switching to another SAC or to a long-acting reversible contraceptive, escalating or combining with second-line therapy (GnRH agonists [e.g., leuprorelin, goserelin, triptorelin] or GnRH antagonists), or considering surgery. 16 , 22 , 48 NSAIDs: Due to the delay in endometrial atrophy induced by sex hormones, hormonal suppression should be initiated concurrently with NSAIDs (if tolerated) for immediate pain control. NSAIDs should be used on a fixed schedule (not ‘as needed’) during pain flares in the first 3 months of treatment. 16 Postoperative prevention: Continuous SACs should begin immediately after conservative surgery to reduce symptoms and endometrioma recurrence. 27 , 43 , 44 , 46 Ovarian cancer screening: Women with endometriosis should receive counseling on increased ovarian cancer risk; long-term SAC use reduces malignant transformation risk. 42 , 45 The main strengths of the present study arise from including data exclusively from systematic reviews and meta-analyses. Moreover, the data extraction was systematically performed by two expert reviewers, with the support of the scientific committee, and following a comprehensive, thoughtful procedure with predefined inclusion criteria, exclusion criteria, classification categories, and standardized data extraction forms. Both the information sources (only systematic reviews and meta-analyses) and the carefully followed procedure ensure the robustness of the included data. The findings of this study provide evidence on SAC benefits beyond contraception that may eventually have an impact on clinical practice guidelines to improve patients care and outcomes. The authors acknowledge several limitations with the present study. First, it is not a systematic review, although an explicit methodology was followed. However, the data included were heterogeneous in terms of study settings, interventions, and measurement variables (including tolerability). The interpretation of findings is further subject to several limitations in the available studies. Most notably, follow-up periods were generally short, and time points for symptom assessment varied across studies, limiting the comparability and generalizability of results. Secondly, the search was performed exclusively in PubMed due to its comprehensive coverage of medical and clinical studies, particularly in the field of gynecology and hormonal contraception. However, using additional databases might have provided a more exhaustive collection of relevant studies. The search covered the 10 previous years of publications (2014–2024), this period was chosen to capture the most recent advances in the field of hormonal contraceptives and their additional benefits, ensuring that the findings are aligned with the latest scientific developments. A language bias cannot be excluded, since only English-written publications were considered. Thirdly, a key limitation of the present review is that adverse effects were not reported in the articles analyzed, and therefore no detailed discussion or results on safety profiles are provided, being a critical factor in clinical decision-making alongside comparative effectiveness. Moreover, the absence of comparative studies for certain SACs may restrict the ability to draw balanced conclusions across formulations. This gap in the evidence underscores the need for future studies to directly assess the comparative efficacy and safety of these regimens. Available evidence does not directly compare EE doses within the same progestin formulation or across continuous vs. cyclic regimens. The range of 15–35 μg reflects different formulation choices rather than evidence of equipotency. Dose-response studies specifically evaluating EE dose within consistent progestin-regimen combinations are needed. Additionally, specific patient populations are underrepresented in the available literature, which may limit the external validity of the findings. Furthermore, the lack of long-term data prevents adequate assessment of sustained efficacy and safety outcomes over extended periods of use. Moreover, this work does not address concomitant pathologies where management may differ, including adenomyosis, fibroids, and non-gynecological conditions; therefore, the considerations presented may not apply in these contexts. Lastly, the practical considerations presented in this article are subject to the biases and perspectives of the contributing authors and may not be generalizable to all clinical settings. Evidence gaps and variability in real-world practice should be considered when applying these considerations.

This review highlights the valuable role of SACs in the treatment of endometriosis beyond their contraceptive function. The evidence supports the efficacy of SACs, especially in continuous regimens, in improving key symptoms such as dysmenorrhea and chronic pelvic pain, as well as preventing disease recurrence following surgical treatment. DSG alone emerges as a particularly effective option, demonstrating superior outcomes compared with several combined formulations in specific symptom domains. However, the choice of formulation and regimen must be personalized, as individual responses and needs vary, and some CHCs may offer advantages in certain subgroups. These findings reinforce the importance of a woman-centered approach to contraceptive prescribing in the context of endometriosis. By integrating the latest evidence into shared decision-making, health care professionals can tailor treatment strategies that optimize outcomes, improve adherence, and address the diverse needs of women living with endometriosis.

This narrative review was conducted under the supervision of a Scientific Committee (SC) composed of experts in endocrine gynecology. While the Agnodice project assessed multiple potential benefits of SACs, the current review specifically examines evidence regarding SAC benefits in endometriosis management. In the Agnodice project, we extracted relevant data from a literature search conducted in PubMed covering studies published between 2014 and 2024. The original search strategy combined terms related to SAC ( e.g., contracep **) with Medical Subject Headings and synonyms for various clinical benefits, including endometriosis. 21 Two reviewers (S.G. and N.T.) alongside the SC assessed the studies’ eligibility by reading the titles and the abstracts of the studies and according to predefined inclusion and exclusion criteria. Publications providing data on the non-contraceptive clinical benefits of SAC when used as contraceptives, i.e., comparative data between SAC versus SAC, SAC and placebo, and SAC versus no treatment, were included. Only systematic reviews and/or meta-analyses in English with available abstracts were included. Studies were excluded if they: (i) were not about contraception; (ii) compared SAC with other type of treatments, (iii) evaluated SAC in combination with other treatments, (iv) analyzed non-SAC contraceptives, or (v) lacked statistical significance testing ( p -values). Finally, the two reviewers thoroughly read the preselected studies to accurately discern whether they were relevant for the review. In case of disagreement, a third reviewer additionally assessed the controversial study, and an agreed decision was reached between the three reviewers. Data from the selected articles were extracted using a standardized data extraction sheet specifically created for this project (see Supplementary Table S1 . for further details). It included key data from each article, and information was extracted as individual items. Any comparison between two or more interventions within a specific population examining specific clinical benefits and outcomes was considered an “item.” According to this definition, each article included may yield several items. To note, in the present study, the term “women” refers to individuals for whom ovulation is biologically expected. Any outcome or benefit specifically related to endometriosis symptoms, progression, or management was considered for inclusion in this sub-analysis. The search strategy, study selection, and data extraction are summarized in Table 1 . Further details of the search, inclusion/exclusion criteria, data extraction, and analysis can be found elsewhere. 21 The Search Strategy, Study Selection, and Data Extraction Summary To note, in the present study, the term “women” refers to individuals for whom ovulation is biologically expected. Practical clinical considerations in the management of endometriosis were generated through an evidence-informed expert synthesis process. The considerations were extracted from the available literature and refined through structured discussion among the authors, integrating real-world clinical experience. A corresponding decision-making pathway was subsequently developed and visually summarized in an infographic figure. These considerations do not constitute formal guidelines or robust recommendations; no formal grading methodology ( e.g., GRADE) was applied. Clinical judgment and adherence to established guidelines should prevail.

Supplemental material, sj-docx-1-whr-10.1177_26884844261476400 for Exploring Short-Acting Hormonal Contraceptives in Endometriosis Care—A Narrative Review and Evidence-Based Practical Considerations by M. Ángeles Martínez-Zamora, Josep Perelló-Capó, Joaquim Calaf-Alsina, and José C. Quílez-Conde